Progress in the development of asymmetric Heck couplings of arenes and acyclic olefins has been limited by a tenuous understanding of the factors that dictate selectivity in migratory insertion and β-hydride elimination. On the basis of key mechanistic insight recently garnered in the exploration of selective Heck reactions, we report here an enantioselective variant that delivers β-, γ-, or δ-aryl carbonyl products from acyclic alkenol substrates. The catalyst system imparts notable regioselectivity during migratory insertion and promotes the migration of the alkene's unsaturation toward the alcohol to ultimately form the ketone product. The reaction uses aryldiazonium salts as the arene source, yields enantiomeric products from opposite starting alkene configurations, and uses a readily accessible ligand. The racemic nature of the alkenol substrate does not bias the enantioselection.

N–N-linked dimeric indole alkaloids represent an unexplored class of natural products for which chemical synthesis has no practical solution. To meet this challenge, an electrochemical oxidative dimerization method was developed, which was applied as the pivotal step of the first total synthesis of dixiamycin B. This method is also general for N–N dimerization of substituted carbazoles and β-carbolines, providing entry into seldom explored chemical space.

A general, highly selective asymmetric redox-relay oxidative Heck reaction using achiral or racemic acyclic alkenols and boronic acid derivatives is reported. This reaction delivers remotely functionalized arylated carbonyl products from acyclic alkenol substrates, with excellent enantioselectivity under mild conditions, bearing a range of useful functionality. A preliminary mechanistic investigation suggests that the regioselectivity of the initial migratory insertion is highly dependent on the electronic nature of the boronic acid and more subtle electronic effects of the alkenyl alcohol.

Conspectus The functional group transformations carried out by the palladium-catalyzed Wacker and Heck reactions are radically different, but they are both alkenyl C-H bond functionalization reactions that have found extensive use in organic synthesis. The synthetic community depends heavily on these important reactions, but selectivity issues arising from control by the substrate, rather than control by the catalyst, have prevented the realization of their full potential. Because of important similarities in the respective selectivity-determining nucleopalladation and β-hydride elimination steps of these processes, we posit that the mechanistic insight garnered through the development of one of these catalytic reactions may be applied to the other. In this Account, we detail our efforts to develop catalyst-controlled variants of both the Wacker oxidation and the Heck reaction to address synthetic limitations and provide mechanistic insight into the underlying organometallic processes of these reactions. In contrast to previous reports, we discovered that electrophilic palladium catalysts with non-coordinating counterions allowed for the use of a Lewis basic ligand to efficiently promote TBHP-mediated Wacker oxidation reactions of styrenes. This discovery led to the mechanistically guided development of a Wacker reaction catalyzed by a palladium complex with a bidentate ligand. This ligation may prohibit coordination of allylic heteroatoms, thereby allowing for the application of the Wacker oxidation to substrates that were poorly behaved under classical conditions. Likewise, we unexpectedly discovered that electrophilic Pd-σ-alkyl intermediates are capable of distinguishing between electronically inequivalent C–H bonds during β-hydride elimination. As a result, we have developed E-styrenyl selective oxidative Heck reactions of previously unsuccessful electronically non-biased alkene substrates using arylboronic acid derivatives. The mechanistic insight gained from the development of this chemistry allowed for the rational design of a similarly E-styrenyl selective classical Heck reaction using aryldiazonium salts and a broad range of alkene substrates. The key mechanistic findings from the development of these reactions provide new insight into how to predictably impart catalyst control in organometallic processes that would otherwise afford complex product mixtures. Given our new understanding, we are optimistic that reactions that introduce increased complexity relative to simple classical processes may now be developed based on our ability to predict the selectivity-determining nucleopalladation and β-hydride elimination steps through catalyst design.

A general, highly selective oxidative Heck reaction is reported. The reaction is high yielding under mild conditions without the need for base or high temperatures, and selectivity is excellent without the requirement for electronically biased olefins, or other specific directing groups. A preliminary mechanistic investigation suggests that the unusually high selectivity may be due to the catalysts sensitivity to C-H bond strength in the selectivity-determining β-hydride elimination step.The oxidative Heck reaction, a transformation in which a vinylic C-H bond is converted to C-C bond under Pd II catalysis, has the potential for broad synthetic applications.1 , 2 Unfortunately, most examples require the use of an electronically biased olefin such as an acrylate to deliver high selectivity for the E-styrenyl product. A notable exception, recently reported by White and coworkers, is proposed to rely on substrate chelation to afford these products as the only observable isomer.3 The poor selectivity under typical Heck conditions presumably arises from a lack of the metal center's ability to distinguish between H S or H A when undergoing β-hydride elimination (eq. 1), resulting in a mixture of often inseparable styrenyl and allylic products.4 Herein, we report a highly selective and general oxidative Heck reaction with a unique preference for the E-styrenyl products governed by catalyst control. Additionally, this reaction does not require base and is efficient at mild temperatures.(1)Recently, we reported an olefin diarylation reaction which utilizes the oxidative Heck mechanistic manifold, but intercepts reactive Pd II -alkyl intermediates with an aryl stannane in a second transmetalation event (eq. 2).5 The success of this system was partially attributed to the cationic nature of the catalyst. Considering the ubiquitous nature of aryl boronic acid derivatives in cross coupling, we choose to evaluate these in our alkene difunctionalization reactions. To our surprise, the use of phenyl boronic ester 4a in the place of the PhSnBu 3 resulted in only E-styrenyl Heck product 5a with no diarylation or isomeric products observed.(2)Optimization of this reaction was performed, wherein raising the temperature to 40 °C resulted in improved yield without diminishing selectivity. Removing molecular sieves and decreasing the Cu(OTf)2 loading further improved the GC yield to >99% in >20:1 selectivity for the E-styrenyl isomer (Table 1). Finally performing the reaction in the absence of the Pd II catalyst, Cu(OTf) 2 or O 2 resulted in little to no reactivity (entries 5-7). Submission of substrate 1a, which is susceptible to β-acetoxy elimination, to the optimized reaction conditions on 0.5 mmol scale resulted in 95% yield of the desired product (Table 2, entry 1).6Considering the unusually high selectivity observed, we chose to examine the scope of this transformation. The reaction proved to be tolerant of a wide variety of functional groups commonly encountered in organic synthesis, delivering the desired E-styrenyl pro...